Dengue Fever

Figure 1: Picture of rash on legs due to dengue fever

Facts You Should Know About Dengue Fever

• Dengue fever is a mosquito-borne viral disease that causes high fevers with headaches and severe muscle and joint pains; a rash may develop.
• Medical care should be sought if a patient develops high fevers; although some patients may be managed at home, patients with dehydration and or other complications like hemorrhage and shock need medical management.
• Treatment of dengue fever, in some patients, requires oral hydration and pain control, usually with Tylenol (acetaminophen) at home; however, patients with more severe infections and those patients with complications like dehydration, hemorrhages, or shock usually need hospital care. Treatment of pain should not include non-steroidal anti-inflammatory drugs (NSAIDs) as they may increase bleeding.
• Prevention is possible in children ages 9-16 with a lab-confirmed previous dengue infection with a vaccine, Dengvaxia, approved by the FDA in the U.S. in 2019. Other countries approved its use in adults up to age 45 in endemic areas.
• Dengue fever is a mosquito-borne viral disease; high fevers, severe muscle, and joint pains, and a rash are the major symptoms and signs.
• The disease has probably been known since the Chinese described it in 420 AD. Outbreaks are increasing although there is no human-to-human transfer, only mosquito-to-human viral transfer (therefore it is not contagious).
• The main risk factor is an Aedes aegypti mosquito bite.
• The disease has a 3- to 15-day incubation period and begins with flu-like symptoms. In most individuals, the disease lasts about 3-10 days, but some symptoms and signs may linger.
• Medical professionals usually diagnose the disease with a blood test (PCR or an immunologic test).
• Adequate hydration and pain control are the usual treatments given to patients treated at home (NSAIDs are not used due to possible bleeding problems; acetaminophen is used instead). There is no home remedy or treatment except for hospital care for severe and complicated infections.
• The majority of people with dengue fever have a complete recovery; however, complications can lead to a worse prognosis.
• Avoiding mosquito bites and/or getting vaccinated with Dengvaxia (subject to age limits) are ways to prevent dengue fever infections.
• The disease has also been termed "breakbone fever" or "dandy fever" because the unusually severe muscle and joint pains can make people assume distorted body positions or exaggerated walking movements in an effort to reduce their pain.

Dengue fever is endemic in tropical and subtropical areas. Dengue fever is estimated by the World Health Organization (WHO) to cause about 50-100 million infections per year worldwide. The U.S. Centers for Disease Control and Prevention (CDC) considers dengue fever to cause the majority of acute febrile illnesses in travelers returning to the U.S. The first clinical report of dengue fever was in 1789 by B. Rush, although the Chinese may have described the disease associated with "flying insects" as early as 420 AD. Africans described "ka dinga pepo" as cramp-like seizure caused by an evil spirit. The Spanish may have changed "dinga" to dengue since it means fastidious or careful in Spanish, which describes the gait of people trying to reduce the pain of walking.

Unfortunately, the disease incidence seems to be increasing. Researchers suggest the surge in dengue fever may be due to several factors:

• Increased urban crowding with more sites for mosquitoes to develop
• International commerce that contains infected mosquitoes, thus introducing the disease to areas previously free of the disease
• Local and world environmental changes that allow mosquitoes to survive the winter months
• International travelers who carry the disease to areas where mosquitoes have not been previously infected

Although dengue is one of the tropical diseases, it has spread widely throughout the world; the CDC distribution map (available at https://wwwnc.cdc.gov/travel/yellowbook/2018/infectious-diseases-related-to-travel/dengue) shows that dengue fever mainly occurs in tropical and subtropical areas. In the U.S., dengue fever has been detected in California, Florida, Texas, and Hawaii. Other areas where it has been detected or there has been an outbreak of the disease include the Philippines, Taiwan, Samoa, South America (Brazil), Puerto Rico, Costa Rica, Southeast Asia, Thailand, and New Delhi. However, as climates warm, experts suggest dengue will become more prevalent.

In 2015, an outbreak of dengue fever occurred in New Delhi, the worst in the previous five years. Over 10,000 people tested positive for dengue fever; there have been at least 32 deaths attributed to this outbreak. State-run hospitals were so overcrowded that patients were sharing beds. An independent group (Brandeis University) suggests the actual numbers of people in India with dengue are "vastly underreported."

A 2017 outbreak of dengue in Sri Lanka reported over 107,000 infections, an unprecedented outbreak. Flooding early in 2017 allowed the mosquito population to flourish and spread the disease; this was a major factor contributing to this outbreak. Sri Lanka's hospitals are converting maternity and other wards to dengue wards, but many are running out of room to treat patients.

Four closely related viruses cause dengue fever. Aedes aegypti and Aedes albopictus mosquitoes spread the viruses to humans in a viral life cycle that requires both humans and these mosquitoes. There is no human-to-human dengue fever transmission.

Once a mosquito is infected, it remains infected for its lifespan. A human can infect mosquitoes when the human has a high number of viruses in the blood (right before symptoms develop). The viruses belong to the Flaviviridae family and have an RNA strand as their genetic makeup.

There are five dengue virus types (DENV-1, DENV-2, DENV-3, DENV-4, and recently, DENV-5; they are also termed DEN-1, DEN-2, DEN-3, DEN-4, and DEN-5 in some publications). All five dengue serotypes are closely related. However, there are enough antigenic differences (antibody-dependent) between them that if a person becomes immune to one serotype, the person can still be infected by the other four serotypes.

The risk factors for dengue fever are as follows:

• Traveling to or living in endemic or outbreak areas, especially if no mosquito control is attempted by the people or government in subtropical areas
• Mosquito bites by Aedes aegypti
• A repeated infection with another serovar of dengue virus with antibodies in the serum active against the first infecting virus type
• Not taking precautions to avoid Aedes mosquitoes

The symptoms and signs of dengue begin about 3-15 days (incubation period) after a mosquito bite transfers a virus (usually dengue virus serotypes 1-4) to a person previously unexposed to the virus. Fever and painful muscle, flu-like symptoms, bone, and joint aches can occur during the first few hours of symptoms when a headache, chills (shivering and/or sweating), rash (may be itchy), and/or red spots or flushing, and swollen lymph nodes first appear. Pain behind or in the back of the eyes (retro-orbital pain) is also a common symptom.

Some individuals may develop a sore throat, vomiting, nausea, abdominal and/or back pain, and loss of appetite. These symptoms usually last about 2-4 days and then diminish, only to reappear again with a rash that covers the body and spares the face. The rash also may occur on the palms of the hands and the bottom of the feet, areas frequently spared in many viral and bacterial infections.

The symptoms and signs may last about one to two weeks with complete recovery, in most cases, in a few weeks. However, some people with the severe form of the virus infection can develop additional symptoms, signs, and complications, such as hemorrhagic areas in the skin (easy bruising), gums, and the gastrointestinal tract. This condition is termed dengue hemorrhagic fever (DHF).

The majority of DHF is seen in children under 15 years of age, but it can occur in adults. Another clinical variation of dengue fever is termed dengue shock syndrome (DSS); DHF usually precedes DSS. The patients eventually develop severe abdominal pain, heavy bleeding, and blood pressure drops; this syndrome, if not treated quickly, may cause death.

Dengue fever is not contagious; it does not spread from person to person. Dengue fever viruses require a vector, a mosquito (see Causes section below), that allows the virus to mature within the mosquito before the mosquito can effectively transfer the viruses to humans during a blood meal.

Symptoms of infection usually start about four to 15 days (the incubation period is typically four to seven days) after a mosquito bite transfers the viruses to the human. In most instances, the disease lasts about three to 10 days, although a few patients' symptoms may last longer.

During the incubation period, large amounts of the virus are present in the person's blood just before the person becomes symptomatic; this is when a mosquito that may be uninfected can pick up viruses that can be transferred to other humans. However, the virus has to develop within the mosquito for a few days before it is ready for transfer during the blood meal (mosquito bite).

A medical caregiver presumptively diagnoses dengue fever by the relatively characteristic sequence of high fever, rash appearance, and other symptoms in a person who has a history of recent travel to dengue endemic areas and recalls mosquito bites while in the endemic area. However, if not all of the symptoms are present or the history is not complete, the caregiver is likely to run a number of tests to obtain a definitive diagnosis.

Other diseases may yield similar symptoms (for example, leptospirosis, typhoid fever, yellow fever, scarlet fever, Rocky Mountain spotted fever, meningococcemia, malaria, chikungunya, food poisoning, and several others). If the patient has severe symptoms, or if the medical caregiver does not have enough information to make a presumptive diagnosis, the patient is likely to undergo a number of other tests to definitively distinguish dengue fever from other diseases. In general, the more serious the symptoms such as easy bruising, fevers at or above 104 F, hemorrhages, or shock syndrome, the more tests are likely to be done.

In general, most physicians will order a complete blood test (CBC), with a metabolic panel, along with coagulation studies in most patients with high fever and any bleeding problems. Low platelet and low white cell counts may occur with the disease. In addition, depending on the symptoms (especially headache), blood and urine cultures plus a spinal tap may be done to help differentiate between dengue fever and other diseases. A MAC-ELISA assay (an immunoglobulin M-based test) is the most widely used test for the dengue fever virus.

However, other tests are available; they also are based on the person's immunological response to the dengue viruses (for example, IgG-ELISA, dengue viral plaque reduction tests, and PCR tests). These tests are definitive for exposure to the dengue virus; definitive diagnosis of dengue fever is isolation and identification (usually by immunological tests) of the dengue virus serovar from the patient.

Fortunately, this viral disease is usually self-limited and usually adequate hydration and pain control will help the person through the infection. Nonsteroidal anti-inflammatory agents (for example, aspirin (Bayer, Ecotrin), ibuprofen (Motrin), and other NSAIDs) should be avoided because of the tendency of the dengue viruses to cause hemorrhages. The NSAIDs may add to the hemorrhage symptoms. Other medications such as acetaminophen (Tylenol), codeine, or other agents that are not NSAIDs may be used.

More severe variations of dengue fever (hemorrhagic and shock syndrome) usually require additional supportive treatments; these patients often require hospitalization. Medical professionals may use IV fluid hydration, blood transfusions, platelet transfusions, blood pressure support, and other intensive care measures in these patients. Consultation with infectious disease and critical care specialists is often advised to optimize patient care.

Home care for dengue fever is simply supportive care. Good oral hydration, pain control with Tylenol (or other non-NSAIDs, because the NSAIDs may cause bleeding) is usually adequate treatment for most people. However, there is no role for home care in patients with dengue hemorrhagic fever or for dengue shock syndrome; depending on the patient's condition, many physicians consider these conditions to be medical emergencies.

Papaya leaf extract helps increase platelet levels in some patients with dengue fever, but researchers caution that definitive studies are not yet available that confirm the utility of this treatment. Patients should consult their doctors before using this remedy.

The complications of dengue fever are usually associated with the more severe forms of dengue fever: hemorrhagic and shock syndrome. The most serious complications, although infrequent, are as follows:

• Dehydration
• Bleeding (hemorrhage)
• Low platelets
• Low blood pressure (hypotension)
• Slow heart rate (bradycardia)
• Liver damage
• Neurological damage (seizures, encephalitis)
• Death

For the large majority of people infected with dengue fever viruses, the prognosis is excellent with complete recovery, although they are likely to feel very ill during the first 1-2 weeks of the acute illness and weak for about one month. Patients with underlying illness or immune suppression have a fair to good prognosis because they are more likely to get complications. Also, people who have been infected by one dengue virus type are still able to be infected by the remaining three types; a second infection increases the possibility that complications will develop, so patients with second-time dengue fever have a less optimal prognosis.

Patients who develop DHF or DSS have a range of outcomes from good to poor, depending on their underlying medical problems and how quickly supportive measures are given. For example, DHF and DSS have about a 50% fatality rate if untreated but only about a 3% rate if treated with supportive measures. Overall, the fatality rate is about 1% for all dengue fever infections. While this rate may seem low, worldwide it means that about 500,000 to 1 million people die each year from dengue fever. This is a concern since the worldwide case numbers and outbreaks are increasing.

It's possible to prevent dengue fever by stopping mosquitoes from biting because they are the vectors the dengue viruses require for transfer to humans. The CDC has supplied these general rules to prevent the transfer of viruses and other pathogens by mosquitoes and other biting vectors, including tick-borne diseases:

• Avoid outbreaks: To the extent possible, travelers should avoid known foci of epidemic disease transmission. The CDC Travelers' Health web page provides alerts and information on regional disease transmission patterns and outbreak alerts (http://www.cdc.gov/travel) or contacts for a travel medicine doctor (often an infectious-disease specialist).
• Be aware of peak exposure times and places: Travelers can reduce their exposure to arthropod bites by modifying their patterns of activity or behavior. Although mosquitoes may bite at any time of day, peak biting activity for vectors of some diseases (for example, dengue, chikungunya) is during daylight hours. Vectors of other diseases (for example, malaria) are most active in twilight periods (for example, dawn and dusk) or in the evening after dark. Avoiding the outdoors or focusing on preventive actions during peak hours may reduce risk. The place also matters; ticks are often found in grasses and other vegetated areas. Local health officials or guides may be able to point out areas with greater arthropod activity.
• Wear appropriate clothing: Travelers can minimize areas of exposed skin by wearing long-sleeved shirts, long pants, boots, and hats. Tucking in shirts and wearing socks and closed shoes instead of sandals may reduce risk. Apply repellents or insecticides such as permethrin (Elimite) to clothing and gear for added protection; this measure is discussed in detail below.
• Bed nets: When accommodations are not adequately screened or air-conditioned, bed nets are essential to provide protection and to reduce discomfort caused by biting insects. If bed nets do not reach the floor, tuck them under mattresses. Bed nets are most effective when treated with an insecticide or repellent such as permethrin. Purchase pretreated, long-lasting bed nets prior to traveling or treat nets after purchase. The permethrin will be effective for several months if the bed net is unwashed. (Long-lasting pretreated nets may be effective for much longer.)
• Insecticides: Aerosol insecticides, vaporizing mats, and mosquito coils can help to clear rooms or areas of mosquitoes; however, some products available internationally may contain pesticides that are not registered in the U.S. Insecticides should always be used with caution, avoiding direct inhalation of spray or smoke.
• Apply repellents: Apply repellents for optimum protection.

The CDC recommends insect repellent should contain up to 50% DEET (N, N-diethyl-m-toluamide), which is the most effective mosquito repellent for adults and children over 2 months of age.

In May 2019, the U.S. FDA approved Dengvaxia (also termed CYD-TDV), the first vaccine approved for each dengue serotype (DENV-1-4) in people ages 9-16 who have had a previously confirmed dengue serotype 1-4 infection. The FDA approved the dengue vaccine for use in the U.S. and its territories. There are about five other companies evaluating clinical trials of dengue virus vaccines.

The following are other sources of information about dengue fever:

"CBRNE - Viral Hemorrhagic Fevers: Multimedia," Medscape.com
http://emedicine.medscape.com/article/
830594-media

"Dengue," U.S. Centers for Disease Control and Prevention
http://www.cdc.gov/dengue/epidemiology/
index.html

"Vector-Borne Viral Infections," World Health Organization
http://www.who.int/vaccine_research/
diseases/vector/en/index.html